Insights Into Laparoscopic Port Site Complications: A Comprehensive Review.

Laparoscopic surgery has become a widely accepted standard of care for numerous procedures in the modern world. Nearly every major surgical procedure previously only possible by employing open techniques may now be completed laparoscopically, attributable to the quick advancement of technology and surgeons' abilities. There are several complications associated with the laparoscopic port site, either infective, non-infective, or neoplastic. This study aims to explore the morbidity associated with the port site following laparoscopic surgery and discuss the risk factors for complications. The umbilical port was most frequently associated with port-site hernia (PSH), followed by the epigastrium and the left and right hypochondrium. Prolonged port manipulation and reinsertion, longer surgical times, failure to effectively close the fascial defect, and wound infection are responsible for the development of PSH. Port-site infection (PSI) is one avoidable adverse effect of laparoscopic surgery. Patients who have a history of diabetes, malnourishment, prolonged preoperative hospital stays, preoperative Staphylococcus aureus colonization of the nares, perioperative blood transfusions, and tobacco or steroid use are more likely to have PSI. Port-site hydatid cyst (PSHC) and port-site tuberculosis (PST) are rare but possible. While uncommon, a doctor should rule out endometriosis if a painful mass in the surgical scar, such as the trocar site, is discovered in a reproductive-age woman who has had pelvic or obstetric surgery in the past. Port-site metastasis (PSM) is the term for tumor-cell implantation at the trocar insertion site after a malignant tumor is removed laparoscopically. PSM has been reported in 1-2% of laparoscopic gynecologic surgical procedures. A few potential mechanisms for cell implantation at the port site include embolization of exfoliated cells during tumor dissection or hematogenous spread, air turbulence during long laparoscopic operations, and direct implantation onto the wound during forced, unprotected organ/tissue retrieval or from contaminated surgical instruments during tumor dissection. Nonetheless, the triggering mechanism is likely essentially multifaceted. Prevention is better than cure. Port-site hernia can be prevented using smaller trocars and meticulous rectus sheath defect closure at the end of surgery. The rest of the port site complications can be prevented by employing autoclavable laparoscopic hand instruments, utilizing autoclaved water to clean the instruments following disassembly, adhering to the recommended concentration, contact duration, and usage cycles when sterilizing instruments with liquid sterilizers, preventing bile or gut content from spilling into the operating room or the port site, using non-porous specimen retrieval bags for recovering the specimen, and thoroughly cleaning and irrigating the port site before closing the wound.

Enhancing Healing Strategies: Negative-Pressure Wound Therapy and Delayed Primary Closure in Abdominal Wounds Post-emergency Laparotomy for Intestinal Perforation.

Background Intestinal perforation is a life-threatening condition requiring immediate surgical intervention. Surgical-site infections (SSIs) and wound dehiscence are common complications associated with emergency laparotomy for intestinal perforation. Finding optimal wound management and postoperative strategies can significantly impact patient outcomes and reduce the risk of complications. Negative-pressure wound therapy (NPWT) is a relatively recent tool employed in the care of wounds to control SSIs and foster healing. Methodology A prospective, observational, cohort study was conducted among 150 patients who underwent emergency exploratory laparotomy due to intestinal perforation at the general surgery department of a tertiary care hospital in New Delhi between July 2022 and December 2023. Preoperatively, all patients underwent initial resuscitation. Intraoperatively, the extent of peritonitis was determined and was categorized according to the Centers for Disease Control and Prevention (CDC) classification. Postoperatively, NPWT dressing was applied to the patient's midline laparotomy wound on postoperative day (POD) two. Negative pressure was set at 75-125 mmHg with suction. The number of NPWT dressing changes required was documented. The wound was closed with vertical mattress sutures under local anesthesia, delayed primary closure (DPC). The incidence of SSIs, the duration for DPC, the incidence of fascial dehiscence, the number of NPWT dressing changes, and the length of hospital stay were documented according to CDC groups. Results The mean age in CDC categories 2, 3, and 4 were 31.789, 28.733, and 42.676 years, respectively. The most common cause of perforation was enteric fever (n = 42, 28%), followed by tuberculosis (n = 36, 24%). Most patients had no known comorbidities (n = 80, 53.3%). Overall, 16% of patients (n = 24) were both alcoholics and smokers. The most frequent bacteria in all CDC categories was Escherichia coli. Fourteen patients developed burst abdomen in the postoperative period and were excluded from the study. The mean duration of DPC increased with higher CDC categories, with CDC category 4 displaying the most extended mean duration at 10.70 days. The number of NPWT dressing changes increases with higher CDC categories, with CDC category 4 exhibiting the highest mean at 2.00 changes. The mean hospital stay increased with higher CDC categories, with CDC category 4 showing the most extended mean stay at 17.324 days. Statistical analysis revealed no significant association between SSI occurrence and CDC categories. Conclusions NPWT followed by DPC is a promising approach to managing gastrointestinal perforations, reducing SSIs, and potentially improving patient outcomes. However, further research is needed to explore the specific benefits of NPWT in conjunction with DPC and its efficacy in various clinical scenarios.

Optimal Timing of Surgical Repair After Bile Duct Injury: A Systematic Review and Meta-Analysis.

BACKGROUND: Major bile duct injury during cholecystectomy often requires surgical reconstruction. The optimal timing of repair is debated. OBJECTIVES: To assess the association between the timing of hepaticojejunostomy and postoperative morbidity, mortality, and anastomotic stricture. METHODS: Systematic review and meta-analysis of observational studies comparing early (<14 days), intermediate (14 days-6 weeks), and late (>6 weeks) repair. Primary outcomes were postoperative morbidity, mortality, and stricture rates. Pooled risk ratios were calculated. A generalized linear model was used to estimate odds per time interval. RESULTS: 20 studies were included in the systematic review. Of these, data from 15 studies was included in the meta-analyses. The 20 included studies comprised a total of 3421 patients who underwent hepaticojejunostomy for bile duct injury. Early repair was associated with lower morbidity versus intermediate repair (RR 0.73, 95% CI 0.54-0.98). Delayed repair had lower morbidity versus intermediate (RR 1.50, 95% CI 1.16-1.93). Delayed repair had a lower stricture rate versus intermediate repair (RR 1.53, 95% CI 1.07-2.20). Mortality was not associated with timing. CONCLUSIONS: Reconstruction between 2 and 6 weeks after bile duct injury should be avoided given the higher morbidity and stricture rates. Delayed repair after 6 weeks may be beneficial.

Comparison of Laparoscopic and Open Pancreaticoduodenectomy on Operative Time, Oncological Outcomes, Bleeding, Morbidity, and Mortality.

Laparoscopic pancreaticoduodenectomy (LPD) has gained popularity as an alternative to open pancreaticoduodenectomy (OPD), but comparative outcomes remain debated. The objective is to perform a systematic review and meta-analysis comparing LPD and OPD on operative time, oncologic outcomes, bleeding, morbidity, and mortality. The inclusion criteria were comparative studies on LPD vs. OPD. Outcomes were pooled using random-effects meta-analysis. A total of 27 studies were included, and LPD had a substantially longer operative duration compared to the OPD procedure, with a mean increase of 56 minutes, but blood loss was reduced by an average of 123 mL in patients who underwent LPD. Morbidity, mortality, margin status, and lymph node yields were similar between LPD and OPD. This study found comparable oncologic outcomes between LPD and OPD. LPD appears safe but requires longer operative time. High-quality randomized trials are still needed.

Single-Stage Laparoscopic Common Bile Duct Exploration and Cholecystectomy Versus Two-Stage Endoscopic Stone Extraction Followed by Laparoscopic Cholecystectomy for Patients With Cholelithiasis and Choledocholithiasis: A Systematic Review.

Gallbladder stones with common bile duct (CBD) stones can be managed by a single-stage laparoscopic approach with transcystic or transcholedochal CBD exploration and cholecystectomy or a two-stage approach with endoscopic retrograde cholangiopancreatography (ERCP) for stone extraction followed by laparoscopic cholecystectomy. Comparative outcomes between these approaches remain controversial. The objective was to compare single-stage laparoscopic CBD exploration and cholecystectomy versus two-stage ERCP stone removal followed by laparoscopic cholecystectomy for clearance of CBD stones, complications, length of stay, and costs. We systematically searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized trials and observational studies comparing outcomes of interest between single and two-stage approaches. Meta-analyses using random effects models were conducted. Seven studies with 382 patients were included. The single-stage approach achieved higher stone clearance rates (OR: 1.53, 95% CI: 1.12-2.08) with a shorter length of stay (mean duration: 3.5 days, 95% CI: -5.1 to -1.9 days) compared to the two-stage method. No significant difference was seen in complication rates (45% vs 40%, p=0.43) or costs ($19,000 vs $18,000, p=0.34). For patients with gallbladder and CBD stones, single-stage laparoscopic CBD exploration with cholecystectomy appears superior for stone clearance while comparable in safety and cost to a two-stage approach. Further randomized trials are warranted.

pH-dependent reaction triggering in PmHMGR crystals for time-resolved crystallography.

Serial crystallography and time-resolved data collection can readily be employed to investigate the catalytic mechanism of Pseudomonas mevalonii 3-hydroxy-3-methylglutaryl (HMG)-coenzyme-A (CoA) reductase (PmHMGR) by changing the environmental conditions in the crystal and so manipulating the reaction rate. This enzyme uses a complex mechanism to convert mevalonate to HMG-CoA using the co-substrate CoA and cofactor NAD+. The multi-step reaction mechanism involves an exchange of bound NAD+ and large conformational changes by a 50-residue subdomain. The enzymatic reaction can be run in both forward and reverse directions in solution and is catalytically active in the crystal for multiple reaction steps. Initially, the enzyme was found to be inactive in the crystal starting with bound mevalonate, CoA, and NAD+. To observe the reaction from this direction, we examined the effects of crystallization buffer constituents and pH on enzyme turnover, discovering a strong inhibition in the crystallization buffer and a controllable increase in enzyme turnover as a function of pH. The inhibition is dependent on ionic concentration of the crystallization precipitant ammonium sulfate but independent of its ionic composition. Crystallographic studies show that the observed inhibition only affects the oxidation of mevalonate but not the subsequent reactions of the intermediate mevaldehyde. Calculations of the pKa values for the enzyme active site residues suggest that the effect of pH on turnover is due to the changing protonation state of His381. We have now exploited the changes in ionic inhibition in combination with the pH-dependent increase in turnover as a novel approach for triggering the PmHMGR reaction in crystals and capturing information about its intermediate states along the reaction pathway.

Survival Secrets: Unmasking the Factors Predicting Failure of Non-operative Management (NOM) in Splenic Injuries.

BACKGROUND: Splenic injuries are common solid organ injuries resulting from blunt abdominal trauma in road traffic accidents. Very often, splenic injuries can be life-threatening. Earlier, splenic injuries were often dealt with surgical intervention, such as splenectomy. With the recognition of the immunological function of the spleen and possible complications of splenectomy surgery, such as overwhelming post-splenectomy infections (OPSI), there has been a recent trend for non-operative management (NOM). OBJECTIVE: To study the variables predicting failure of NOM in blunt abdominal trauma patients with splenic injury. METHODS: This is a retrospective study that includes 235 patients who presented to the Safdarjung Hospital emergency room (New Delhi, India) with blunt trauma abdomen and splenic injuries with or without associated injuries between January 2019 and December 2021. The data was entered in a Microsoft Excel spreadsheet (Microsoft Corp., Redmond, WA, USA). Categorical variables were expressed as frequencies and percentages. Pearson's chi-square test of association was used to determine if there is a relationship between two variables. A p-value of <0.05 was considered statistically significant. RESULTS: Out of 235 patients with blunt abdominal trauma and splenic injuries, 82 were hemodynamically unstable despite resuscitation and were taken up for emergency laparotomy. The remaining 153 patients, who were either hemodynamically stable or stabilized after adequate resuscitation, were managed on the lines of NOM. The number of patients with splenic injury in AAST grades 1, 2, 3, 4, and 5 was 36, 50, 40, 24, and three, respectively. Out of 153 patients, 130 (85%) were successfully managed by NOM, while eight (5%) had to discontinue NOM as they required surgical intervention. The failure of NOM (fNOM) is seen mostly with grade 5 injuries (2/2, 100%, p<0.01), followed by grade 4 (4/20, 20%) and grade 3 (2/37, 5.7%). The mean age in fNOM was 58.3 years, as compared to 42.2 years in the success of NOM (sNOM). All eight patients had multiple concomitant injuries, with femur fracture being the most common association in up to six patients (p<0.01), followed by liver injury in four patients. There were 15 mortalities, irrespective of AAST severity grade. All of these patients had associated concomitant injuries, with intracranial bleeding (n = 10, 32%, p<0.01) being the most common association, followed by femur fracture (n = 6, 20%) and liver injury (n = 5, 16%). Also, the cause of death was unrelated to splenic trauma (p = 0.67), with pulmonary embolism (n = 6, 40%, p<0.01) being the most common cause, followed by brain stem herniation (n = 5, 34%). CONCLUSION: Non-operative management is a safe and efficient method for treating patients with splenic injuries who are hemodynamically stable or stabilized. The factors associated with fNOM include elderly age, a higher American Association for the Surgery of Trauma (AAST) grade of splenic injury, and associated concomitant injuries. Femur fracture was the most common concomitant injury present in cases where NOM failed, followed by liver injury. The presence of intracranial bleeds in these patients was a common association with mortality, irrespective of the grade of splenic injury.

A Literature Review of the Effects of Air Pollution on COVID-19 Health Outcomes Worldwide: Statistical Challenges and Data Visualization.

Several peer-reviewed papers and reviews have examined the relationship between exposure to air pollution and COVID-19 spread and severity. However, many of the existing reviews on this topic do not extensively present the statistical challenges associated with this field, do not provide comprehensive guidelines for future researchers, and review only the results of a relatively small number of papers. We reviewed 139 papers, 127 of which reported a statistically significant positive association between air pollution and adverse COVID-19 health outcomes. Here, we summarize the evidence, describe the statistical challenges, and make recommendations for future research. To summarize the 139 papers with data from geographical locations around the world, we also present anopen-source data visualization tool that summarizes these studies and allows the research community to contribute evidence as new research papers are published.

Revolutionizing Breast Healthcare: Harnessing the Role of Artificial Intelligence.

Breast cancer has the highest incidence and second-highest mortality rate among all cancers. The management of breast cancer is being revolutionized by artificial intelligence (AI), which is improving early detection, pathological diagnosis, risk assessment, individualized treatment recommendations, and treatment response prediction. Nuclear medicine has used artificial intelligence (AI) for over 50 years, but more recent advances in machine learning (ML) and deep learning (DL) have given AI in nuclear medicine additional capabilities. AI accurately analyzes breast imaging scans for early detection, minimizing false negatives while offering radiologists reliable, swift image processing assistance. It smoothly fits into radiology workflows, which may result in early treatments and reduced expenditures. In pathological diagnosis, artificial intelligence improves the quality of diagnostic data by ensuring accurate diagnoses, lowering inter-observer variability, speeding up the review process, and identifying errors or poor slides. By taking into consideration nutritional, genetic, and environmental factors, providing individualized risk assessments, and recommending more regular tests for higher-risk patients, AI aids with the risk assessment of breast cancer. The integration of clinical and genetic data into individualized treatment recommendations by AI facilitates collaborative decision-making and resource allocation optimization while also enabling patient progress monitoring, drug interaction consideration, and alignment with clinical guidelines. AI is used to analyze patient data, imaging, genomic data, and pathology reports in order to forecast how a treatment would respond. These models anticipate treatment outcomes, make sure that clinical recommendations are followed, and learn from historical data. The implementation of AI in medicine is hampered by issues with data quality, integration with healthcare IT systems, data protection, bias reduction, and ethical considerations, necessitating transparency and constant surveillance. Protecting patient privacy, resolving biases, maintaining transparency, identifying fault for mistakes, and ensuring fair access are just a few examples of ethical considerations. To preserve patient trust and address the effect on the healthcare workforce, ethical frameworks must be developed. The amazing potential of AI in the treatment of breast cancer calls for careful examination of its ethical and practical implications. We aim to review the comprehensive role of artificial intelligence in breast cancer management.

Piezosurgery Versus Conventional Method Alveoloplasty: A Comparative Study.

Purpose: The conventional alveoloplasty approach which uses manual equipment results in more resorption of the underlying alveolar ridge that makes denture prosthesis unstable. The goal of this study was to compare results of piezosurgery alveoloplasty to those of conventional alveoloplasty. Materials and Methods: This was an in-vivo comparative study consisting of ten edentulous individuals who needed alveoloplasty due to bilateral bony projection. On one side, a conventional alveoloplasty was performed with a bone rongeur and bone file, whereas the contralateral side was treated with a piezosurgery unit. The clinical parameters were analyzed using SPSS version 21 software including operating time, postoperative pain evaluation on day 3 and a healing on day 7. Results: There was a statistically significant difference between the two groups in terms of outcome variables such as operating time, pain and healing. The Conventional group has a lower mean of operating time, a higher mean rank of VAS and a lower mean rank of healing index compared to the piezosurgery group. Conclusion: Piezosurgery alveoloplasty not only lowers postoperative patient discomfort but also preserves alveolar bone integrity by not disrupting soft and hard tissue architecture thus allowing faster tissue healing and easier prosthesis replacement in the future.

Optimal policies for mitigating pandemic costs: a tutorial model.

There have been a number of pharmaceutical and non-pharmaceutical interventions associated with COVID-19 over the past two years. Various non-pharmaceutical interventions were proposed and implemented to control the spread of the COVID-19 pandemic. Most common of these were partial and complete lockdowns that were used in an attempt to minimize the costs associated with mortality, economic losses and social factors, while being subject to constraints such as finite hospital capacity. Here, we use a minimal model posed in terms of optimal control theory to understand the costs and benefits of such strategies. This allows us to determine top-down policies for how to restrict social contact rates given an age-structured model for the dynamics of the disease. Depending on the relative weights allocated to mortality and socioeconomic losses, we see that the optimal strategies range from long-term social-distancing only for the most vulnerable, partial lockdown to ensure not over-running hospitals, and alternating-shifts, all of which lead to significant reduction in mortality and/or socioeconomic losses. Crucially, commonly used strategies that involve long periods of broad lockdown are almost never optimal, as they are highly unstable to reopening and entail high socioeconomic costs. Using parameter estimates from data available for Germany and the USA early in the pandemic, we quantify these policies and use sensitivity analysis in the relevant model parameters and initial conditions to determine the range of robustness of our policies. Finally we also discuss how bottom-up behavioral changes affect the dynamics of the pandemic and show how they can work in tandem with top-down control policies to mitigate pandemic costs even more effectively.

BNT162b2 Vaccine Effectiveness against Omicron in Children 5 to 11 Years of Age.

BACKGROUND: Limited evidence is available on the real-world effectiveness of the BNT162b2 vaccine against coronavirus disease 2019 (Covid-19) and specifically against infection with the omicron variant among children 5 to 11 years of age. METHODS: Using data from the largest health care organization in Israel, we identified a cohort of children 5 to 11 years of age who were vaccinated on or after November 23, 2021, and matched them with unvaccinated controls to estimate the vaccine effectiveness of BNT162b2 among newly vaccinated children during the omicron wave. Vaccine effectiveness against documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and symptomatic Covid-19 was estimated after the first and second vaccine doses. The cumulative incidence of each outcome in the two study groups through January 7, 2022, was estimated with the use of the Kaplan-Meier estimator, and vaccine effectiveness was calculated as 1 minus the risk ratio. Vaccine effectiveness was also estimated in age subgroups. RESULTS: Among 136,127 eligible children who had been vaccinated during the study period, 94,728 were matched with unvaccinated controls. The estimated vaccine effectiveness against documented infection was 17% (95% confidence interval [CI], 7 to 25) at 14 to 27 days after the first dose and 51% (95% CI, 39 to 61) at 7 to 21 days after the second dose. The absolute risk difference between the study groups at days 7 to 21 after the second dose was 1905 events per 100,000 persons (95% CI, 1294 to 2440) for documented infection and 599 events per 100,000 persons (95% CI, 296 to 897) for symptomatic Covid-19. The estimated vaccine effectiveness against symptomatic Covid-19 was 18% (95% CI, -2 to 34) at 14 to 27 days after the first dose and 48% (95% CI, 29 to 63) at 7 to 21 days after the second dose. We observed a trend toward higher vaccine effectiveness in the youngest age group (5 or 6 years of age) than in the oldest age group (10 or 11 years of age). CONCLUSIONS: Our findings suggest that as omicron was becoming the dominant variant, two doses of the BNT162b2 messenger RNA vaccine provided moderate protection against documented SARS-CoV-2 infection and symptomatic Covid-19 in children 5 to 11 years of age. (Funded by the European Union through the VERDI project and others.).

Diabetes Mellitus With Renal and Müllerian Anomalies.

OBJECTIVE: Maturity-onset diabetes of the young (MODY) type 5 is caused by an autosomal dominant mutation in the HNF1B gene. Our objective was to report a case of a young girl with bicornuate uterus and recurrent renal stones with diabetes mellitus (DM) without a family history that was diagnosed to be MODY 5. CASE REPORT: A 12-year-old girl presented with recurrent renal stones that were managed with lithotripsy and double-J stenting at various time points. At the age of 14 years, she was found to have a bicornuate uterus with an absent cervix and vagina. She was diagnosed with DM at the age of 16 years without a preceding history of osmotic symptoms or steatorrhea. Although there was no family history of young-onset diabetes, given her long-standing history of müllerian abnormalities, renal cysts, and pancreatic hypotrophy, she was evaluated for MODY. Using the next-generation sequencing, she was found to be positive for a reported HNF1B gene pathogenic mutation c.494G>A (p.Arg165His), confirming a diagnosis of MODY 5. DISCUSSION: There is a significant overlap in clinical criteria for type 2 DM and MODY in the Asian Indian population. The HNF1B gene mutation is difficult to diagnose as none of the clinical manifestations are pathognomonic and many lack a family history of DM. Diagnostic algorithms with specific clinical and biochemical criteria along with pancreatic imaging can help in case detection and direct toward particular genetic mutation analysis. CONCLUSION: We suggest that genetic testing be offered to patients with otherwise unexplained DM and such genitourinary anomalies.

Mixed Methods Evaluation of Reasons Why Care Deviates From Clinical Guidelines Among Patients With Multimorbidity.

Reasons why care does not conform to single-disease guideline recommendations for multimorbid patients have not been systematically measured in practice. Using a mixed methods approach, we identified and quantified types of reasons why care deviates from nine sets of disease guideline recommendations for multimorbid patients. Utilizing a focus group concept mapping technique, we built on a categorization of reasons explaining guideline deviation, and surveyed treating nurses about these reasons for patients' specific care processes. Directed content analysis was conducted to classify the responses into reasons categories. Of 4,386 guideline-recommended care processes evaluated, 920 were not guideline-concordant (944 reasons). Three broad categories of reasons and 18 specific reasons were identified: Biomedical-related occurred 35.2% of the time, patient personal-related (30.4%), context-related (18.4%), and unknown (16.0%). Patient- and context-related factors are prevalent drivers for guideline deviation in multimorbidity, demonstrating that patient-centered aspects are as much a part of care decisions as biomedical aspects.

Loss of H3K27 methylation identifies poor outcomes in adult-onset acute leukemia.

BACKGROUND: Acute leukemia is an epigenetically heterogeneous disease. The intensity of treatment is currently guided by cytogenetic and molecular genetic risk classifications; however these incompletely predict outcomes, requiring additional information for more accurate outcome predictions. We aimed to identify potential prognostic implications of epigenetic modification of histone proteins, with a focus on H3K4 and H3K27 methylation marks in relation to mutations in chromatin, splicing and transcriptional regulators in adult-onset acute lymphoblastic and myeloid leukemia. RESULTS: Histone 3 lysine 4 di- and trimethylation (H3K4me2, H3K4me3) and lysine 27 trimethylation (H3K27me3) mark expression was evaluated in 241 acute myeloid leukemia (AML), 114 B-cell acute lymphoblastic leukemia (B-ALL) and 14T-cell ALL (T-ALL) patient samples at time of diagnosis using reverse phase protein array. Expression levels of the marks were significantly lower in AML than in B and T-ALL in both bone marrow and peripheral blood, as well as compared to normal CD34+ cells. In AML, greater loss of H3K27me3 was associated with increased proliferative potential and shorter overall survival in the whole patient population, as well as in subsets with DNA methylation mutations. To study the prognostic impact of H3K27me3 in the context of cytogenetic aberrations and mutations, multivariate analysis was performed and identified lower H3K27me3 level as an independent unfavorable prognostic factor in all, as well as in TP53 mutated patients. AML with decreased H3K27me3 demonstrated an upregulated anti-apoptotic phenotype. In ALL, the relative quantity of histone methylation expression correlated with response to tyrosine kinase inhibitor in patients who carried the Philadelphia cytogenetic aberration and prior smoking behavior. CONCLUSION: This study shows that proteomic profiling of epigenetic modifications has clinical implications in acute leukemia and supports the idea that epigenetic patterns contribute to a more accurate picture of the leukemic state that complements cytogenetic and molecular genetic subgrouping. A combination of these variables may offer more accurate outcome prediction and we suggest that histone methylation mark measurement at time of diagnosis might be a suitable method to improve patient outcome prediction and subsequent treatment intensity stratification in selected subgroups.

Guideline deviation and its association with specific chronic diseases among patients with multimorbidity: a cross-sectional cohort study in a care management setting.

OBJECTIVES: To assess whether the extent of deviation from chronic disease guideline recommendations is more prominent for specific diseases compared with combined-care across multiple conditions among multimorbid patients, and to examine reasons for this deviation. DESIGN: A cross-sectional cohort. SETTING: Multimorbidity care management programme across 11 primary care clinics. PATIENTS: Patients aged 45-95 years with at least two common chronic conditions, sampled according to being new (≤6 months) or veteran (≥1 year) to the programme. MAIN OUTCOME MEASURES: Deviation from guideline-recommended care was measured for each patient's relevant conditions, aggregated and stratified across disease groups, calculated as measures of 'disease-specific' guideline deviation and 'combined-care' (all conditions) guideline deviation for: atrial fibrillation, congestive heart failure, chronic kidney disease, chronic obstructive pulmonary disorder, depression, diabetes, dyslipidaemia, hypertension and ischaemic heart disease. Combined-care deviation was evaluated for its association with specific diseases. Frequencies of previously derived reason types for deviation (biomedical, patient personal and contextual) were reported by nurse care managers, assessed across diseases and evaluated for their association with specific diseases. RESULTS: Among 204 patients, disease-specific deviation varied more (from 14.7% to 48.2%) across diseases than combined-care deviation (from 14.7% to 25.6%). Depression and diabetes were significantly associated with more deviation (mean: 6% (95% CI: 2% to 10%) and 5% (95% CI: 2% to 9%), respectively). For some conditions, assessments were among small patient samples. Guideline deviation was often attributed to non-disease-specific reasons, such as physical limitations or care burden, as much as disease-specific reasons, which was reflected in the likelihood for guideline deviation to be due to different types of reasons for some diseases. CONCLUSIONS: When multimorbid patients are considered in disease groups rather than as 'whole persons', as in many quality of care studies, the cross-cutting factors in their care delivery can be missed. The types of reasons more likely to occur for specific diseases may inform improvement strategies. TRIAL REGISTRATION NUMBER: NCT01811173; Pre-results.

A phase 1, single centre, open label, escalating dose study to assess the safety, tolerability and immunogenicity of a therapeutic human papillomavirus (HPV) DNA vaccine (AMV002) for HPV-associated head and neck cancer (HNC).

BACKGROUND: We conducted a phase 1 dose escalation study (ACTRN12618000140257 registered on 30/01/2018) to evaluate the safety, tolerability and immunogenicity of a therapeutic human papillomavirus (HPV) DNA vaccine (AMV002) in subjects previously treated for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). METHODS: Eligible subjects had to have no evidence of recurrent and/or metastatic disease at least 12 weeks following the completion of treatment. Three dosing cohorts each consisted of four subjects: group 1: 0.25 mg/dose, group 2: 1 mg/dose, group 3: 4 mg/dose. AMV002 was delivered intradermally on days 0, 28 and 56. Incidence and severity of treatment-emergent adverse events (TEAE) including local reaction at the injection site, and vaccination compliance were recorded. T cell and antibody responses to HPV16 E6 and E7 were measured by interferon gamma (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assay and enzyme-linked immunosorbent assay (ELISA). RESULTS: All subjects completed the vaccination programme and experienced mild discomfort at the injection site(s). Pre-immunisation, cell-mediated responses to HPV16 E6 and E7 were evident in all subjects, and E7-specific antibodies were detected in 11 (91.7%), reflecting previous exposure to HPV. Post-vaccination, 10 of 12 (83.3%) subjects responded to one or more of the E6 and/or E7 peptide pools, while 2 (16.7%) did not show additional vaccine-induced cell-mediated responses. Vaccination resulted in a ≥ 4-fold increase in anti-HPV16 E7 antibody titre in one subject in group 3. CONCLUSIONS: AMV002 was well tolerated at all dose levels and resulted in enhanced specific immunity to virus-derived tumour-associated antigens in subjects previously treated for HPV-associated OPSCC.

Assessing guideline-concordant care for patients with multimorbidity treated in a care management setting.

BACKGROUND: Disease-specific guidelines are not aligned with multimorbidity care complexity. Meeting all guideline-recommended care for multimorbid patients has been estimated but not demonstrated across multiple guidelines. OBJECTIVE: Measure guideline-concordant care for patients with multimorbidity; assess in what types of care and by whom (clinician or patient) deviation from guidelines occurs and evaluate whether patient characteristics are associated with concordance. METHODS: A retrospective cohort study of care received over 1 year, conducted across 11 primary care clinics within the context of multimorbidity-focused care management program. Patients were aged 45+ years with more than two common chronic conditions and were sampled based on either being new (≤6 months) or veteran to the program (≥1 year). MEASURES: Three guideline concordance measures were calculated for each patient out of 44 potential guideline-recommended care processes for nine chronic conditions: overall score; referral score (proportion of guideline-recommended care referred) and patient-only score (proportion of referred care completed by patients). Guideline concordance was stratified by care type. RESULTS: 4386 care processes evaluated among 204 patients, mean age = 72.3 years (standard deviation = 9.7). Overall, 79.2% of care was guideline concordant, 87.6% was referred according to guidelines and patients followed 91.4% of referred care. Guideline-concordant care varied across care types. Age, morbidity burden and whether patients were new or veteran to the program were associated with guideline concordance. CONCLUSIONS: Patients with multimorbidity do not receive ~20% of guideline recommendations, mostly due to clinicians not referring care. Determining the types of care for which the greatest deviation from guidelines exists can inform the tailoring of care for multimorbidity patients.

Translating clinical trial results into personalized recommendations by considering multiple outcomes and subjective views.

Currently, clinicians rely mostly on population-level treatment effects from RCTs, usually considering the treatment's benefits. This study proposes a process, focused on practical usability, for translating RCT data into personalized treatment recommendations that weighs benefits against harms and integrates subjective perceptions of relative severity. Intensive blood pressure treatment (IBPT) was selected as the test case to demonstrate the suggested process, which was divided into three phases: (1) Prediction models were developed using the Systolic Blood-Pressure Intervention Trial (SPRINT) data for benefits and adverse events of IBPT. The models were externally validated using retrospective Clalit Health Services (CHS) data; (2) Predicted risk reductions and increases from these models were used to create a yes/no IBPT recommendation by calculating a severity-weighted benefit-to-harm ratio; (3) Analysis outputs were summarized in a decision support tool. Based on the individual benefit-to-harm ratios, 62 and 84% of the SPRINT and CHS populations, respectively, would theoretically be recommended IBPT. The original SPRINT trial results of significant decrease in cardiovascular outcomes following IBPT persisted only in the group that received a "yes-treatment" recommendation by the suggested process, while the rate of serious adverse events was slightly higher in the "no-treatment" recommendation group. This process can be used to translate RCT data into individualized recommendations by identifying patients for whom the treatment's benefits outweigh the harms, while considering subjective views of perceived severity of the different outcomes. The proposed approach emphasizes clinical practicality by mimicking physicians' clinical decision-making process and integrating all recommendation outputs into a usable decision support tool.